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Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.
Khan, SS, Post, WS, Guo, X, Tan, J, Zhu, F, Bos, D, Sedaghati-Khayat, B, van Rooij, J, Aday, A, Allen, NB, et al
JAMA. 2023;(20):1768-1777
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Abstract
IMPORTANCE Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. OBJECTIVE To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. DESIGN, SETTING, AND PARTICIPANTS Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. EXPOSURE Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. MAIN OUTCOMES AND MEASURES Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. RESULTS The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). CONCLUSIONS AND RELEVANCE In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.
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Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study.
Kingwell, E, Zhang, T, Zhu, F, Walld, R, Carruthers, R, Evans, C, Marrie, RA, Tremlett, H
Expert opinion on drug safety. 2021;(4):481-487
Abstract
BACKGROUND Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users. METHODS Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs). RESULTS Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT. CONCLUSIONS The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.
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Metabolomics analysis of the serum from children with urolithiasis using UPLC-MS.
Wen, J, Cao, Y, Li, Y, Zhu, F, Yuan, M, Xu, J, Li, J
Clinical and translational science. 2021;(4):1327-1337
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Abstract
Pediatric urolithiasis is a common urologic disease with high morbidity and recurrence rates. Recent studies have shown that metabolic dysfunction plays a vital role in the pathogenesis of urolithiasis, especially in children, but the specific mechanism is still unclear. Metabolomics is an ideal technology for exploring the mechanism of metabolic disorders in urolithiasis. In the present study, a serum metabolomics based on ultra-performance liquid chromatography mass spectrometry was performed. A total of 50 children subjects were recruited for the study, including 30 patients with kidney stones and 20 normal controls (NCs). Principal component analysis and orthogonal partial least-squares determinant analysis were carried, and 40 metabolites were found to be significantly altered in patients with kidney stones, mainly involving retinol metabolism, steroid hormone biosynthesis, and porphyrin and chlorophyll metabolism. The kidney stone group appeared to have a lower serum level of bilirubin, but a relative higher level of retinal, all-transretinoic acid, progesterone, and prostaglandin E2 compared with those of the NC group. All the findings suggest that patients with urolithiasis have several metabolic characteristics, which are related to stone formation or compensation. These metabolites and pathways are very likely associated with development of kidney stones and should be considered as potential novel targets for treatment and prevention.
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Adherence to disease-modifying therapies for multiple sclerosis and subsequent hospitalizations.
Evans, C, Marrie, RA, Zhu, F, Leung, S, Lu, X, Kingwell, E, Zhao, Y, Tremlett, H
Pharmacoepidemiology and drug safety. 2017;(6):702-711
Abstract
PURPOSE The aim of this study was to examine the association between optimal adherence to first-line disease-modifying therapies (DMT) for multiple sclerosis (MS) and hospitalizations. METHODS We used population-based administrative data from three Canadian provinces. All individuals receiving DMT (interferon-B-1b, interferon-B-1a, or glatiramer acetate) between January 1, 1996, and December 31, 2011 (British Columbia); March 31, 2012 (Manitoba); or March 31, 2014, (Saskatchewan) were included. Adherence was estimated for the first year of DMT (year 0), using the medication possession ratio (MPR). The association between optimal adherence (MPR ≥ 80%) and all-cause and MS-specific hospitalizations in the subsequent 1, 2, and 5 years was assessed using Hurdle Poisson and logistic regression. Rate and odds ratios were adjusted (aRR and aOR) for sociodemographic factors and prior health-care utilization. RESULTS Overall, 4746 subjects were followed for a mean 7.8 (SD 4.0) years; 3598 (76%) were women. Optimal DMT adherence was achieved in 3564/4746 (75.1%) subjects. Subsequent all-cause and MS-specific hospitalizations were lower for subjects with optimal versus suboptimal adherence, but none reached statistical significance (1-year period, aRR = 0.77, 95%CI: 0.47-1.26; aOR = 0.80, 95%CI: 0.52-1.25). Similar findings were observed in the 2-year and 5-year periods. Prior health-care utilization (hospitalizations and medications) was associated with future hospitalizations; for every additional medication class, the 5-year all-cause hospitalization rate and likelihood of an MS-specific hospitalization increased by 5% and 11%, respectively (aRR = 1.05, 95%CI: 1.02-1.07; and aOR = 1.11, 95%CI: 1.07-1.14). CONCLUSIONS Hospitalization rates were lower in subjects with optimal DMT adherence, but findings were not statistically significant. Prior hospitalization and polypharmacy were associated with increased risk for future hospitalizations in MS. Copyright © 2017 John Wiley & Sons, Ltd.
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Assessment of cancer risk with β-interferon treatment for multiple sclerosis.
Kingwell, E, Evans, C, Zhu, F, Oger, J, Hashimoto, S, Tremlett, H
Journal of neurology, neurosurgery, and psychiatry. 2014;(10):1096-102
Abstract
OBJECTIVE The risk of cancer after exposure to the β-interferons (IFNβs) for multiple sclerosis (MS) has not been established. We assessed whether IFNβ treatment for MS is associated with cancer risk or the risk of specific cancers in a population-based observational study. METHODS The British Columbia MS database was linked to the provincial Cancer Registry, Vital Statistics death files and Health Registration files. Using a nested case-control design, MS cancer cases were matched with up to 20 randomly selected MS controls at the date of cancer diagnosis by sex, age (± 5 years) and study entry year using incidence density sampling. Associations between treatment exposure and overall or specific (breast, colorectal, lung and prostate) cancers were estimated by conditional logistic regression, adjusted for MS disease duration and age. Tumour size at cancer diagnosis was compared between treated and untreated patients using the stratified Wilcoxon test to explore potential lead time bias. RESULTS The cohort included 5146 relapsing-onset MS patients and 48,705 person-years of follow-up, during which 227 cancers were diagnosed. Exposure to IFNβ was not significantly different for cases and controls (OR 1.28; 95% CI 0.87 to 1.88). There was a non-significant trend towards an increased risk of IFNβ exposure in the breast cancer cases (OR 1.77; 95% CI 0.92 to 3.42), but no evidence of a dose-response effect. Tumour size was similar between IFNβ treated and untreated cases. CONCLUSIONS There was no evidence of an increased cancer risk with exposure to IFNβ over a 12-year observation period. However, the trend towards an association between IFNβ and breast cancer should be investigated further.